tbuckley/cabot-search huggingface dataset:
The Identification and Validation of Plasma Membrane Proteins as Potential Therapeutic Targets for Histone H3 Mutant Paediatric High-Grade Gliomas
Authors: Anya Snary, Farhana Haque, James Pickering, Ruman Rahman, Richard Grundy, Robert Layfield
Journal: Neuro-Oncology (2022)

Abstract AIMS Paediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death in children. Histone H3.3 mutations are an important hallmark of pHGG, but for which their underlying oncogenic mechanisms are incompletely understood. This research aims to identify potential molecular effectors in these tumours that may be therapeutically effective. METHOD To assess potential molecular effectors, we employed proteomic profiling using LC-MS/MS and determined plasma membrane proteins of the surfactome that are differentially expressed on the surface of H3.3 mutant (G34R, G34V), compared to H3.3-wildtype human glioma cells in culture. RESULTS Profiling of plasma membrane-enriched fractions identified 34 membrane proteins exclusively detected from H3 G34V mutant cells compared to H3 wild-type cells, and 10 membrane proteins exclusively detected from H3 G34R mutant cells, with 39 membrane proteins shared between both H3 G34R/V genotypes. One of these shared membrane proteins, GLUT1 (glucose transporter) has very recently been reported to be over-expressed and linked to tumour phenotypes in mouse glioma cells manipulated to carry the most common DIPG-associated H3.3-K27M mutation [Miya et al. Neuro-Oncology Advances 2021]. Here, we explore the functional significance of GLUT1 differential expression in H3.3 mutant (G34R, G34V) human glioma cells.
Hippocampal Dosimetry and Neurocognitive Function in Patients Undergoing Stereotactic Radiosurgery for Brain Metastases
Authors: Sahar Iqbal, Maeve Williams, Michelle Smalley, Tara Daisley-Devoy, Richard Wise, John Staffurth, Jillian Maclean, Owen Tilsley, James Powell
Journal: Neuro-Oncology (2022)

Abstract AIMS To measure neurocognitive function (NCF) and correlate with hippocampus dose in patients undergoing stereotactic radiosurgery (SRS) for 1-3 brain metastases. METHOD We conducted a prospective observational study measuring NCF before and after SRS in patients with 1-3 brain metastases and correlated changes with hippocampal dosimetry Patients underwent NCF testing at baseline, 1 month, 3 months and 6 months post SRS and quality of life was measured at each time point. NCF tests included Hopkin’s Verbal learning test, controlled oral word association test and trail making tests. Hippocampus was outlined in line with RTOG guidance and dose was collected from the treatment planning system. RESULTS 36 patients were recruited. Mean age was 64 years, median WHO performance status 1 (range 0-2). At baseline, 65% of patients displayed NCF impairment in at least 1 NCF domain and 33% didn’t exhibit any neurological symptoms. Asymptomatic patients has underlying diagnosis of non-small cell lung cancer or melanoma. NCF impairment was evident at 1, 3 and 6 months for 50%, 66% and 40% patients respectively. Decline at 1 month was associated with higher median dose to 0.1cc of hippocampus (5 Gy vs 2.35 Gy). Association with hippocampal dose and NCF impairment at 3 and 6 months was not observed. CONCLUSION A significant proportion of patients exhibited impaired NCF at baseline with greatest NCF decline seen at 1 months and subsequent recovery of NCF evident at 6 months. Dose to hippocampus 0.1cc may be associated with acute NCF toxicity. Main limitations of this study was small number of patients.
Prolonged Transfusion-Dependent Temozolomide-Induced Thrombocytopaenia in Glioblastoma: Risk Factors Remain Elusive
Authors: Nashwah Ismail, Karan Patel, Rovel Colaco, Gerben Borst, Dusan Milanovic, Catherine McBain
Journal: Neuro-Oncology (2022)

Abstract AIMS Temozolomide-induced thrombocytopaenia is well-recognised; clinical-course varies widely. Aims: To identify risk factors for prolonged thrombocytopaenia; improve patient-care; inform trial design. METHOD Glioblastoma (GBM) patients requiring platelet transfusion were identified. (Local policy: transfuse when plt count ≤ 30 x 109/L). Inclusion criteria: First-line-standard-of-care temozolomide-chemo-radiotherapy (TMZ-CRT). Case-notes reviewed for demographics, blood-counts, radiotherapy and treatment parameters. Thrombocytopaenia grading: CTCAE V5. Date of onset measured from start of TMZ-CRT to date of platelets &amp;lt; 100 x 109/L, and to date of first instance of ≥ grade 3 thrombocytopaenia. Thrombocytopaenia duration: time to platelet count recovery to ≥ 100x109/L. RESULTS Between 2017-2021, 69 patients required platelet transfusion; 68/69 identified on routine monitoring. 49 patients were analysed (6:no CRT; 5:trial study drug; 7:≥ 2nd line treatment; 2:inadequate data). Median age: 59 (range 25-73); 61% female. First incidence of thrombocytopaenia during concurrent TMZ-CRT: 27/49 patients; during adjuvant TMZ in 22/49 (13/22 following 6-week-TMZ-CRT, 9/22 following 3-week-TMZ-CRT). In concurrent patients, median time to thrombocytopaenia: 33 days (range 23-38); median duration: 44 days (range 20-105; 5 not recovered); number of transfusions: 1-2:9 pts; 3-4:6pts; 5-7:3pts; 8-10:7pts; &amp;gt;10:2pts. Of 22 adjuvant patients transfused, 8/22 developed ≥G3 thrombocytopaenia post-cycle-2; 19/22 resolved after 1 or 2 transfusions. Thrombocyopaenia was associated with ≥G3 neutropaenia in 11% of patients requiring &amp;lt;5 transfusions vs 75% requiring ≥ 5. Comparison of &amp;lt; 5 vs ≥ 5 transfusion-patients did not identify differences in any demographic or treatment parameters. CONCLUSION Risk factors for prolonged TMZ-induced thrombocytopenia vs swiftly-resolving thrombocytopaenia remain elusive. This needs to be reflected in consent processes and in design of clinical trials.
Photodynamics of Subependymal Giant Cell Astrocytoma (SEGA) with 5-Aminolevulinic Acid (5-ALA/Gliolan©)
Authors: Imran Ghani, Sabina Patel, Istvan Bodi, Francesco Vergani, Keyoumars Ashkan, Ranjeev Bhangoo, Jose Pedro Lavrador
Journal: Neuro-Oncology (2022)

Abstract AIMS 5-ALA (Gliolan©) is a valuable surgical tool used predominantly in high grade tumours, which utilises tissue fluorescence to improve the visualisation of the brain-tumour interface. This ensures safe maximal resection, while preserving healthy brain. While Gliolan© use in low grade tumours has previously been reported with variable results, reports of its use and success in the context of SEGA are extremely rare. This report highlights the use of Gliolan© in a patient presenting with a Subependymal Giant Cell Astrocytoma (in a background of tuberous sclerosis), facilitating maximal safe resection and preserving eloquent tissue. METHOD Tumour resection was performed with pre-operative DTI-fiber tracking and mapping. A transsulcal minimal invasive parafascicular approach (tsMIPS) was carried out with assistance of NICO BrainPath© tubular retractor system (60x13.5), neuronaviagtion, Gliolan©, intra-operative neuro monitoring (IONM), and ultrasound guidance RESULTS The tumour was found to have both bright and pale fluorescence in the cystic and solid components respectively. Resection was limited to the soft cystic component only, as the solid tumour component showed anatomical attachment to the subgenual area and the fornix. No fluorescence was perceived at the end of resection. The patient made a good recovery with no post-operative deficits. Histopathology confirmed subependymal giant cell astrocytoma (SEGA, WHO grade I). No adjuvant treatment was required CONCLUSION This reports suggests 5-ALA may be beneficial in the safe resection of SEGAs. Further studies and technological advances in the area of photodynamics, imaging, and intra-operative mapping may be helpful to fully evaluate the efficacy of 5-ALA in SEGAs and other low-grade tumours.
The Two-Week-Wait Referral Pathway: Not Fit for Purpose
Authors: Almira Moosa, Jeremy Rees
Journal: Neuro-Oncology (2022)

Abstract AIMS The two-week-wait (2WW) referral pathway was set up by the Department of Health to improve early diagnosis and overall survival of cancer. Brain tumours, however, present with non-specific neurological symptoms. As such, this study set out to evaluate the efficacy of the 2WW pathway in detecting brain cancer in patients referred by primary care. METHOD Data from 217 patients referred via the 2WW pathway from January to September 2021 were extracted retrospectively, using the electronic health record system within the University College London NHS Foundation Trust. Details of the diagnoses, imaging results, and follow-up treatments were analysed. RESULTS Of the 217 patients referred with a suspected brain tumour, 0 patients received a new diagnosis of brain cancer. However, 4 cases of benign tumours were newly diagnosed through the 2WW pathway, with an additional 17 cases of benign tumours being referred for further management, having been detected on previous external imaging. 9 cases of known malignant brain tumours were referred for on-going management, having been treated previously elsewhere. CONCLUSION The 2WW pathway does not detect new cases of brain cancer. It is rather being used as a means of rapid referral of patients in primary care with benign tumours or previously identified brain cancer. This study therefore suggests that the initial aspiration of detecting brain cancer earlier via this pathway has not been fulfilled, but it is a useful tool for GPs to refer patients with brain tumours into Neuro-oncology services.
Usability of Mixed Reality in Awake Craniotomy Planning
Authors: Richard Moon, Neil Barua
Journal: Neuro-Oncology (2022)

Abstract AIMS This study aimed to describe our institutional use of a commercially available mixed reality viewer within a multi-disciplinary planning workflow for awake craniotomy surgery and to report an assessment of its usability. METHOD Three Tesla MRI scans, including 32-direction diffusion tensor sequences, were reconstructed with BrainLab Elements auto-segmentation software. Magic Leap mixed reality viewer headsets were registered to a shared virtual viewing space to display image reconstructions. System Usability Scale was used to assess the usability of the mixed reality system. RESULTS The awake craniotomy planning workflow utilises the mixed reality viewer to facilitate a stepwise discussion through four progressive anatomical layers; skin, cerebral cortex, subcortical white matter tracts and tumour with surrounding vasculature. At each stage relevant members of the multi-disciplinary team reviewed key operative considerations, including patient positioning, cortical and subcortical speech mapping protocols and surgical approaches to the tumour. The mixed reality system was used in 10 consecutive awake craniotomy procedures over a 5-month period. Ten participants (2 Anaesthetists, 5 Neurosurgical trainees, 2 Speech therapists, 1 Neuropsychologist) completed System Usability Scale assessments, reporting a mean score of 71.5. Feedback highlighted the benefit of being able to rehearse important steps in the procedure, including patient positioning and anaesthetic access and visualising the testing protocol for cortical and subcortical speech mapping. CONCLUSION This study supports the use of mixed reality for multi-disciplinary planning for awake craniotomy surgery, with an acceptable degree of interface usability. We highlight the need to consider the requirements of non-technical, non-neurosurgical team members when involving mixed reality activities.
Cross-protective humoral immunity to coronaviruses from SARS coronavirus 2–naïve sera of children with Kawasaki disease
Authors: Tzu-Yi Lin, Yu-Lin Lee, Kun-Lang Wu, Ming-Chun Yang, Chi-Nan Huang, Chun-Min Fu, Li-Ming Huang, Luan-Yin Chang, Ming-Tai Lin, Hong-Hsing Liu
Journal: Clinical Microbiology and Infection (2022)
Patient Information on Awake Craniotomy: A Video Leaflet
Authors: Gemma Wall, Gill Cooke, Erminia Albanese, Stephen Merron, Huan Chan, Lloyd Craker, Michael Owen
Journal: Neuro-Oncology (2022)

Abstract AIMS An Awake Craniotomy is a neuro-surgical procedure where the patient remains awake for all or part of their surgery to allow a lesion to be maximally resected without damaging healthy brain functioning. An annual audit of our Patient Satisfaction Survey demonstrated that ‘Receiving Written Information’ was scoring below standard. A new leaflet was designed to address this and it was developed into a ‘Video Leaflet’ comprising a 10 minute audio-visual production, accessed by QR code. METHOD The team created a scripted description of the patient Awake Craniotomy experience. The script was coded into: audio narration, written information or video content. The areas covered were: consultations with the team; pre and intra-operative testing; fMRI scanning; hospital environments; and follow-up. The script was filmed with written consent from all involved and then collated by the Communications Department. There were several revisions made based on feedback from all involved resulting in the final product. RESULTS The Video Leaflet is ready to be demonstrated to and evaluated by patients using a structured questionnaire. The annual audit of Satisfaction Surveys will be compared prior to and post the introduction of the Video Leaflet to determine whether ratings for ‘Receiving Written Information’ have improved. Questionnaire results which are available by the conference date will be presented as preliminary findings. CONCLUSION It is anticipated that the Video Leaflet will further optimise patient preparation, facilitate informed consent and contribute to maximising coping and engagement from a patient perspective to improve patient experience for a complex and daunting procedure.
Hull’s Magic Box: Keeping Brain Tumour Biopsies “Alive” in the Lab Brings Research Opportunities for New Therapies and Earlier Diagnosis of Brain Tumour
Authors: Antonia Barry, Sabrina Samuel, Amr Moursi, Srihari Deepak, Shailendra Achawal, Chittoor Rajaraman, Lauric Feugere, Alexander Iles, Vicky Green, Mark Wade, Lucy Stead, John Greenman, Pedro Beltran-Alvarez
Journal: Neuro-Oncology (2022)

Abstract AIMS Assess/evaluate apoptosis in GBM samples maintained on a microfluidics system in response to GSK3368715 and other PRMT inhibitors, currently in clinical trials, with the ultimate goal of synergising with personalised patient care and precision medicine. Investigate the effect of treating GBM biopsies on-chip with PRMT inhibitors at the molecular level, including RNA and protein modifications. METHOD GBM biopsies are received from Hull Royal Infirmary and maintained on-chip for 8-days. They are perfused with media, at a rate of 3 μl/min, mimicking the in vivo environment and allowing real-time analysis of tumour behaviour. PRMT inhibitors, such as GSK3368715, are added to the media, in conjunction with TMZ, to determine their efficacy ex vivo using a range of techniques, such as: immunohistochemistry, cell viability assays, protein analysis and RNA-sequencing. RESULTS We show that PRMT inhibition increases apoptosis five-fold above the control, untreated GBM-on-chip samples. This is compounded by cell viability assays, which have indicated that cell viability in these post-chip tissues is reduced by 30% upon treatment with 1μM GSK3368715. Additionally, western blot analysis has indicated that PRMT inhibition with GSK3368715 appears to switch the methylation status of fused-in-sarcoma (FUS) protein in GBM biopsies. CONCLUSION These results indicate that PRMT inhibition may not only be a viable target for GBM therapy, but could also highlight a mechanism for re-sensitising MGMT-negative GBM to TMZ. This data produces an exciting argument for further research into the use of this novel inhibitor for improving prognosis for patients diagnosed with this devastating disease.
Temozolomide Sensitivity of Malignant Glioma Cell Lines – A Systematic Review Assessing Consistencies Between In Vitro Studies
Authors: Michael T C Poon, Morgan Bruce, Joanne Simpson, Cathal Hannan, Paul Brennan
Journal: Neuro-Oncology (2022)

Abstract AIMS Malignant glioma cell line models are integral to pre-clinical testing of novel potential therapies. Accurate prediction of likely efficacy in the clinic requires that these models are reliable and consistent. We assessed this by examining the reporting of experimental conditions and sensitivity to temozolomide in glioma cells lines. METHOD We searched Medline and Embase (Jan 1994-Jan 2021) for studies evaluating the effect of temozolomide monotherapy on cell viability of at least one malignant glioma cell line. Key data items included type of cell lines, temozolomide exposure duration in hours (hr), and cell viability measure (IC50). RESULTS We included 212 studies from 2789 non-duplicate records that reported 248 distinct cell lines. The commonest cell line was U87 (60.4%). Only 10.4% studies used a patient-derived cell line. The proportion of studies not reporting each experimental condition ranged from 8.0–27.4%, including base medium (8.0%), serum supplementation (9.9%) and number of replicates (27.4%). In studies reporting IC50, the median value for U87 at 24 h, 48 h and 72 h was 123.9 μM (IQR 75.3–277.7 μM), 223.1 μM (IQR 92.0–590.1 μM) and 230.0 μM (IQR 34.1–650.0 μM), respectively. The median IC50 at 72 h for patient-derived cell lines was 220 μM (IQR 81.1–800.0 μM). CONCLUSION Temozolomide sensitivity reported in comparable studies was not consistent between or within malignant glioma cell lines. Drug discovery science performed on these models cannot reliably inform clinical translation. A consensus model of reporting can maximise reproducibility and consistency among in vitro studies.
Newly Diagnosed Brain Tumours: When Is a Staging CT Required?
Authors: Ahmad Mahmoud El-Sayed Ali, John Anthony Doherty, Anastasios Benjamin Konteas, Amir Ali Varasteh, Noorulain Iqbal, Hemanth Vupputuri, Andrew Brodbelt
Journal: Neuro-Oncology (2022)

Abstract AIMS Newly diagnosed brain lesions (NBL) on imaging can be either primary or secondary in nature. Of these, only secondary brain lesions routinely require a staging CT chest, abdomen, and pelvis (CTCAP). But owing to lack of clear guidelines, all NBLs usually receive a staging investigation. This leads to over investigation of primary brain tumors. We sought to identify predictors of secondary brain lesions using CT head alone to guide the selection of patients for a CTCAP. METHOD Patients with NBLs referred to a tertiary Neurosurgical centre were reviewed. For protocol creation, data was collected from patients referred between July to December 2020, potential predictor variables were identified. Potential candidate protocols identified were assessed in a protocol-testing stage using data from a different set of patients. Sensitivity, specificity, and area under the curve (AUC) values were computed for each protocol. RESULTS The protocol-creation stage included 222 patients. Multivariate logistic regression analysis identified candidate protocols. This identified the most sensitive predictors of metastatic disease as : a previous history of cancer, multiple lesions, lesion size &amp;lt;4cm, and infratentorial location. A final protocol identified was found to have a sensitivity of 99.1% (AUC 0.704). CONCLUSION The use of the above protocol derived from this study would reduce unnecessary CTCAPs by 37.5-40% overall. Patients who do not fulfil at least one of the above said criteria on the first assessment should not have a CTCAP initially. This protocol reduces the financial and time costs from unnecessary CTCAPs as well as reduces patient exposure to radiation and contrast.
A Comparative Proteomic Analysis of the Cell Membrane of Histone 3 Mutated Paediatric High-Grade Gliomas in order to Identify Potential Immunotherapeutic Targets
Authors: Farhana Haque
Journal: Neuro-Oncology (2022)

Abstract AIMS Improvements in the treatments for childhood and adolescent brain tumours, High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), have not advanced much and they continue to carry a very poor prognosis. These brain tumours are now defined by mutations affecting histone 3 proteins, indeed 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. We hypothesized that the histone 3 mutant tumours will have distinct mutation specific surfactome or cell surface proteins. We analysed the cell surface proteomics of H3.3 G34V and G34R mutated high-grade glioma in comparison to the H3 wild-type Glioma, to explore whether these proteins have the potential to be used as immunotherapeutic targets. METHOD We have at first isolated the cell membrane fractions from a range of patient cells carrying histone 3 mutations (G34R, G34V) relative to wild type histone 3. A comparative quantitative liquid chromatographic mass- spectrometry analyses of these cell surface membrane fractions were performed to identify specific targetable factors. RESULTS The results of these were analysed with the focus in identifying proteins that can be targeted for tumour specific immune modulation or immunotherapeutic intervention. CONCLUSION Results of these analyses will be presented.
Comparative Analysis of the Histone H3 Mutant Protein Interactome Landscape in Paediatric High-Grade Gliomas
Authors: Farhana Haque
Journal: Neuro-Oncology (2022)

Abstract AIMS There have been no significant improvements in the treatments for childhood and adolescent High-Grade Glioma (pHGG) and Diffuse Intrinsic Pontine Glioblastoma (DIPG), which have a very poor prognosis. These cancers harbour mutations affecting histone 3 (H3) proteins, 80% of DIPGs harbour histone H3.1 and H3.3 K27M somatic mutations whilst 30% of pHGGs exhibit H3.3 G34R or G34V mutations. Several studies have highlighted the epigenetic changes associated with these mutations, however their precise role in tumourigenesis is still unknown. We hypothesize that H3 mutations promote an aberrant interaction landscape and analysis of these interactome will highlight important pathophysiological consequences in these tumours. METHOD Two different affinity chromatographic proteomic analyses were performed using different recombinant H3 wild type (WT) and H3 mutant histone proteins (K27M, G34R and G34V) to purify their binding partners, from cell extracts of control and pHGG/DIPG patients cell lines. The purified samples were then subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) to identify their co-bound partners. RESULTS The results have isolated unique and common differential interaction partners of the H3 mutants and with cellular proteins in comparison to H3 WT protein, in the pHGG tumour cells. CONCLUSION The role these altered protein interactions are being investigating in tumour initiation, progression and/or maintenance of H3 mutated pHGG/DIPG, with the aim to manipulate their function as alternate therapeutic intervention. Results of these analyses/experiments will be presented.